Ultra-high pressure liquid chromatography apparatus to study the pharmacokinetics of small molecules

这项提议旨在发展一种能力来量化生物介质中的低水平循环分子。它旨在支持由NSERC资助的三个研究小组的研究，这些小组在药物化学(Marsault)、分子成像(LPage)和干细胞研究(Bentzinger)方面具有互补的专业知识。Marsault的研究旨在确定大周期细胞渗透性的结构决定因素，这类分子在药物发现中正引起越来越大的兴趣。为此，他对大环肽进行了修饰，以了解微妙的修饰如何影响其渗透性，这对进一步将其用作口服药物非常重要。同样重要的是能够确定这些分子的代谢命运。本辛格的研究旨在表征肌肉干细胞如何响应并与环境相互作用。在这方面，他已经确定了环境中对干细胞命运至关重要的一些关键因素。他现在正在识别影响干细胞命运的小分子，这些小分子需要在体内进行量化。*利佩奇的研究旨在开发更好的方法，对正电子发射断层扫描和磁共振成像中使用的成像探针进行药代动力学建模。在这方面，为了在体内量化成像探针与其目标相互作用的能力，他需要能够获得能够量化低水平示踪剂的分析设备。所需的仪器--配备紫外线检测器和馏分收集器的超高性能液相色谱仪(UPLC)将与现有的串联MS/MS仪器耦合。这两种仪器的结合将提供分析生物体液中非常低水平的化合物所需的高灵敏度。这一能力对于支持三个共同申请者的项目以及与学术和工业团体的更多合作至关重要。在生物科学更加依赖和严重依赖高性能分析能力的背景下，这种专门知识对于培训高素质人员也至关重要。

This proposal aims at developing a capacity for the quantification of low-level circulating molecules in biological media. It is intended to support the research of three NSERC-funded research groups with complementary expertise in medicinal chemistry (Marsault), molecular imaging (Lepage) and stem cell research (Bentzinger).******Marsault's research aims at identifying the structural determinants of cellular permeability of macrocycles, a class of molecules that is drawing increasing levels of interest in drug discovery. Toward this end, he modifies macrocyclic peptides to understand how subtle modifications influence their permeability, which is important to further use them as oral drugs. It is equally important to be able to determine the metabolic fate of these molecules.******Bentzinger's research aims at characterizing how muscle stem cells respond and interact with their environment. In that respect, he has identified some key elements of the environment that are important for stem cells fate. He is now in the process of identifying small molecules that influence stem cell fate that will need to be quantified in vivo.******Lepage's research aims to develop better methods for pharmacokinetic modeling of imaging probes used in positron emission tomography and magnetic resonance imaging. In that respect, in order to quantify in vivo the ability of imaging probes to interact with their target, he needs access to an analytical equipment able to quantify low levels of tracers.******The required instrument, a UltraHigh Performance Liquid Chromatography (UPLC) equipped with a UV detector and a fraction collector, will be coupled to an existing tandem MS/MS instrument. The combination of these two instruments will provide the high level of sensibility required to analyze very low levels of compounds in biological fluids. This capacity is critical to support the programs of the three co-applicants, as well as additional collaborations with academic and industrial groups. This expertise is also critical for the training of highly qualified personnel in a context where biological sciences rely more and are heavily on high performance analytical capacities.